Sickle cell disease (SCD) is a global health issue that affects over 13 million people worldwide, including ~100,000 Americans. SCD is a chronic and multifactorial disease, which is characterized by a persistent milieu of oxidative stress, inflammation, and painful episodes of sickle crisis. The Product and Long-Term Goal: Nanometics is developing a targeted small molecule enzyme inhibitor as an acute therapeutic for sickle crisis. It is anticipated that this new immunomodulatory approach will be useful to expedite the time to reach resolution of crisis. The Technological Innovation: The Nanometics approach utilizes a targeted enzyme inhibitor with high specificity and picomolar affinity to block metabolism of an endogenous anti-inflammatory molecule and allow for its accumulation to therapeutically beneficial levels. Phase I Hypotheses: This Phase I SBIR will demonstrate the feasibility of the Nanometics enzyme inhibitor as an oral therapeutic for acute crisis. The hypotheses that will be tested during the Phase I SBIR experiments are that a single oral dose of the inhibitor will be: 1) as effective as a single intraperitoneal dose; and 2) will convey a therapeutic benefit for > 24 h. Specific Aims: Specific Aim 1. Demonstrate the pharmacological and concentration dependent effects of a single oral dose of MTDIA in the microvasculature of BERK mice. Phase II: Phase II SBIR studies will establish the mechanism of action and regulatory toxicity profile. Commercial Application: Each year in the U.S., there are approximately 190,000 emergency room visits by patients seeking treatment for sickle crisis. There is no commercial therapeutic to avert imminent episodes of crisis or to reduce the time to resolution of crisis once it has begun.